Purpose: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate, whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.
Experimental Design: [ Telomerase reverse transcriptase (TERT) ] promoters were sequenced in 182 MPM samples and compared to clinicopathological characteristics. Surgical specimens from 45 MPM patients were tested for in vitro immortalization….
Results: [ Telomerase reverse transcriptase (TERT) ] promoter mutations were detected in 19/182 (10.4%) MPM cases and significantly associated with advanced disease and non-epithelioid histology. Mutations independently predicted shorter overall survival in both histological MPM subtypes. Moreover, 9/9 (100%) mutated but only 13/36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered….
Conclusions: [ Telomerase reverse transcriptase (TERT) ] promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
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